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PubMed2003

Novel mutations involving the NF1 gene coding sequence in neurofibromatosis type 1 patients from Taiwan.

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome affecting the nervous system. The disease is one of the most common autosomal dominant diseases in all ethnic groups. Although the gene was mapped to human chromosome 17 and isolated in 1990, the detection of NF1 mutation is still considered to be a challenge as the gene is large and contains multiple exons. Here we report the detection of three genomic mutations in three Chinese patients living in Taiwan. A DNA diagnosis procedure was established to investigate the NF1 gene mutation at both the transcript and genomic DNA levels. Mutations causing transcript alteration were uncovered in three patients. In the first case, we detected a deletion involving exons 39-45 (nucleotide 7260-8167 in GenBank accession No. M89914). In the second case, a 2199-2448 deletion resulted in skipping of exon 13. The third case skipped the exon 3 in the mutant transcript. We further investigated what caused the cDNA deletion by PCR using genomic DNA as a template. In the first patient, we identified an approximately 17.5 kbp deletion in the NF1 gene. In the other two patients, we identified a single-base substitution (IVS13+1G>A) at the splicing donor site in the second case, and an IVS3+1G>T substitution in the third case. We conclude that genomic deletion and alteration of splicing signal caused abnormal transcripts and truncated proteins in the three Taiwanese NF1 cases.

DNA Mutational Analysis↗
PubMed2000

The parental origin of new mutations in neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (P=0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.

Adolescent↗
PubMed1999

Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis.

Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by formation of multiple schwannomas and meningiomas due to inactivating mutations in the NF2 tumor suppressor gene on chromosome 22. We describe a polymorphism in the 3' untranslated region of the NF2 gene that is informative in about one-third of individuals. This polymorphism permitted an assessment of the relative expression of NF2 transcripts in lymphoblastoid cell RNA from 22 unrelated NF2 patients heterozygous for a germline NF2 mutation, along with 6 schwannomatosis patients, and 14 unaffected controls. Unequal allelic expression (1.8- to 20-fold) was detected in 15 of the NF2 cases, but in none of the schwannomatosis or control individuals. Underexpression of the NF2 mutant allele was documented for all 6 nonsense or frameshift mutations, 3 of 6 splice mutations, and 1 of 4 missense mutations, which, unexpectedly, was shown to alter the NF2 transcript and create a premature stop codon. In contrast, equal expression or slight overexpression of NF2 mutant alleles was observed for 2 in-frame deletions, 2 splice alterations, and 3 missense mutations. In the remaining 5 cases, the allele representing the mutant transcript was not known. Thus, truncating NF2 mutations, which are the most frequent alterations in NF2 patients and NF2-associated tumors, were associated with underexpression of the mutant allele, whereas the less common in-frame alterations usually showed normal or slight overexpression of the mutant transcript.

Alleles↗
PubMed2005

Neurofibromatosis 2 (NF2) and malignant mesothelioma in a man with a constitutional NF2 missense mutation.

Neurofibromatosis 2 (NF2) is caused by inactivating mutations of the NF2 tumor suppressor gene. Somatic NF2 mutations also occur in a high proportion of human primary malignant mesotheliomas. We report an elderly man with NF2, malignant mesothelioma, and a constitutional NF2 missense mutation. The long latent period for mesothelioma in this patient (61 years) raises the possibility that the type of mutant NF2 allele could affect mesothelioma tumorigenesis or progression.

Aged↗
PubMed2007

Molecular diagnosis of neurofibromatosis type 1: 2 years experience.

Our experience of providing an NF1 gene diagnostic mutation detection service as part of the U.K. Genetic Testing Network (UKGTN) is presented. A total of 169 unrelated individuals suspected of having neurofibromatosis type I (NF1) were referred for NF1 diagnostic testing over a 2 year period. Mutation analysis of the entire NF1 coding region and the flanking splice sites was carried out, and included the use of a combination of FISH, dHPLC and MLPA. Possible disease causing mutations were identified in 109 (64%) cases. These comprised 88 different sequence alterations, of which 57 were novel. Out of the 169 cases referred, there were 102 patients with reliable clinical data, of whom 78 satisfied the NIH diagnostic criteria for NF1. Within this better defined cohort of NF1 patients, NF1 mutations were identified in 61 individuals (78%), showing the importance of clinical selection on overall test sensitivity, and highlighting the problem of full clinical data collection in the audit of routine services. As mutation detection technologies advance, facilitating direct sequencing of all coding and flanking non-coding regions of the NF1 gene, the development of an even more cost-effective, quick and sensitive diagnostic test for future testing of NF1 is discussed.

Alternative Splicing↗
PubMed2007

Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited conditions. A range of complications has been described, including gastrointestinal manifestations. Gastric carcinoid tumours are associated with multiple endocrine neoplasia, atrophic gastritis and pernicious anaemia but have not been reported in NF1 in the absence of other predisposing factors. We report the occurrence and investigation of a gastric carcinoid tumour in a 23-year-old woman with previously uncomplicated NF1. Analysis of the tumour tissue revealed loss of heterozygosity at the NF1 gene locus but a normal karyotype and an absence of microsatellite instability. A germline NF1 gene nonsense mutation in exon 37 was detected by denaturing high-performance liquid chromatography and DNA sequence analysis. This is the first reported occurrence of a gastric carcinoid tumour in a patient with NF1 in the absence of other predisposing factors such as pernicious anaemia. The analyses indicate that the carcinoid arose through NF1 gene inactivation but in the absence of an inherited NF1 gene microdeletion. This case adds to the range of gastrointestinal tumours that may be encountered in patients with NF1, particularly in those who present with upper gastrointestinal haemorrhage.

Adult↗
PubMed2001

Diagnosis and management of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose major feature is the occurrence of multiple neurofibromas, which are benign tumors of the nerve sheath. It affects an estimated one in 3000 to 4000 individuals. In addition to neurofibromas, there are many other clinical manifestations, including malignant tumors such as gliomas or malignant peripheral nerve sheath tumors, and nontumor effects such as skeletal dysplasia and learning disability. Diagnosis is established on the basis of clinical criteria. Molecular genetic testing is feasible, but the large size of the gene and wide range of pathogenic mutations have so far impeded the development of a clinical diagnostic test. Insights into pathogenesis have followed from identification of the NF1 gene and the development of animal models. The major function of the gene product appears to be regulation of the ras protein. Tumors are believed to arise by the loss of function of the NF1 protein, suggesting that NF1 behaves as a tumor suppressor gene. Heterozygous effects on some cell types are also likely, however. The role of ras in the pathogenesis of tumors in NF1 has suggested an approach to treatment using ras inhibitors, some of which are likely to begin in clinical trials in NF1 patients in the near future.

Animals↗
PubMed1992

Neurofibromatosis.

The two types of neurofibromatosis are NF-1 and NF-2. Both cause abnormal cell growth in the central and peripheral nervous system. Each disease is inherited as an autosomal dominant trait, thus each child of an affected parent has a 50% chance of inheriting the disorder. Because there is no cure for either type of NF and treatment consists of amelioration of clinical symptoms, genetic counseling is the only preventive approach to this disease.

Genetic Counseling↗
PubMed1991

Identification and characterization of the gene for neurofibromatosis type 1.

Elucidation of the partial genomic structure and DNA sequence of the gene responsible for neurofibromatosis type 1, and discovery of clues to its function, have led to new opportunities not only for understanding this particular disease process, but also for clarifying signalling pathways involved in cellular growth and differentiation.

Cell Differentiation↗
PubMed1991

Identification and characterization of the gene for neurofibromatosis type 1.

Elucidation of the partial genomic structure and DNA sequence of the gene that is altered in neurofibromatosis type 1, and the discovery of clues to its function, have opened new opportunities not only for understanding this particular disease process but also for clarifying signal pathways involved in cellular growth and differentiation. (This review is an updated and modified version of a review first published in Current Opinion in Genetics and Development 1991, 1:15-19.)

Genes, Neurofibromatosis 1↗
PubMed2006

Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is the most common cancer predisposition syndrome. NF1 patients present with a constellation of clinical manifestations and have an increased risk of developing certain benign and malignant tumors. This disease results from mutation within the gene encoding neurofibromin, a GTPase activating protein (GAP) for Ras. Functional loss of this protein compromises Ras inactivation, which leads to the aberrant growth and proliferation of neural crest-derived cells and, ultimately, tumor formation. Current management of NF1-associated malignancy involves radiation, surgical excision, and cytotoxic drugs. The limited success of these strategies has fueled researchers to further elucidate the molecular changes that drive tumor formation and progression. This discussion will highlight how intracellular signaling molecules, cell-surface receptors, and the tumor microenvironment constitute potential therapeutic targets, which may be relevant not only to NF1-related malignancy but also to other human cancers.

Animals↗
PubMed2006

Two neurofibromatosis type 1 cases associated with rhabdomyosarcoma of bladder, one with a large deletion in the NF1 gene.

Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder, affecting approximately 1 in 3,500 individuals worldwide. Mutations of the NF1 tumor suppressor gene predispose individuals to a variety of benign and malignant tumors. Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma and is also a rare tumor type in NF1 patients. We report two cases of NF1 with RMS. The first is that of an infant with overlapping phenotypic features of NF1 and Noonan syndrome (NS) who presented with RMS of the bladder. The second infant likewise exhibited NF1 features and was also associated with bladder RMS. DNA samples were extracted from peripheral blood and tumor tissue samples. We performed loss of heterozygosity (LOH) analysis of the NF1 gene by using seven intragenic markers (IVS27AAAT2.1, IVS27EVI-20, IVS27AC24.8, IVS27AC28.4, M98509, IVS27AC33.1, IVS38TG53.0) and one extragenic polymorphic marker (3'NF1). A large deletion was detected in the NF1 gene in the NF1-Noonan syndrome (NF-NS) case associated with RMS.

Gene Deletion↗
PubMed2025

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

PURPOSE: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). METHODS: We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. RESULTS: Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions. CONCLUSION: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

Humans↗
PubMed2007

A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1.

Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

Animals↗
PubMed2004

Neuroimaging findings in neurofibromatosis type 1 and 2.

Neuroimaging, particularly MR imaging, plays an important role in the diagnosis and management of the patient with neurofibromatosis type 1 and 2. These phakomatoses are complex disorders affecting multiple cell types and multiple systems of the body with a wide range of expression. This article summarizes the neuroradiologic central nervous system findings in these neurocutaneous disorders.

Bone Diseases↗
PubMed2001

NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors.

Although plexiform neurofibroma (PN) is thought to represent a benign neoplasm with the potential for malignant transformation (malignant peripheral nerve sheath tumor; MPNST), its neoplastic nature has been difficult to prove due to cellular heterogeneity, which hampers standard molecular genetic analysis. Its mixed composition typically includes Schwann cells, fibroblasts, perineurial-like cells, and mast cells. Although NF1 loss of heterozygosity has been reported in subsets of PNs, it remains uncertain which cell type(s) harbor these alterations. Using a dual-color fluorescence in situ hybridization and immunohistochemistry technique, we studied NF1 gene status in S-100 protein-positive and -negative cell subpopulations in archival paraffin-embedded specimens from seven PNs, two atypical PNs, one cellular/atypical PN, and eight MPNSTs derived from 13 patients, seven of which had neurofibromatosis type 1 (NF1). NF1 loss was detected in four of seven PNs and one atypical PN, with deletions entirely restricted to S-100 protein-immunoreactive Schwann cells. In contrast, all eight MPNSTs harbored NF1 deletions, regardless of S-100 protein expression or NF1 clinical status. Our results suggest that the Schwann cell is the primary neoplastic component in PNs and that S-100 protein-negative cells in MPNST represent dedifferentiated Schwann cells, which harbor NF1 deletions in both NF1-associated and sporadic tumors.

Adolescent↗
PubMed1992

Familial neurofibromatosis type 1: clinical experience with DNA testing.

To determine how DNA testing for familial neurofibromatosis type 1 (NF-1) would be used in a clinical setting by patients and physicians, we performed confirmatory DNA testing on 24 individuals with a family history of NF-1 and on nine couples who requested DNA testing for current or future prenatal diagnosis. A further eight families were unsuitable for DNA linkage testing because of their pedigree structure. For the majority of persons the certainty of the test result was 95% to 99%. In five individuals, only one of whom was less than 6 years of age, the DNA-based diagnosis was discrepant with the clinical diagnosis at the time of referral. In all five cases, results of subsequent clinical re-examinations were consistent with the DNA diagnosis. We conclude that DNA testing by linkage analysis may be most useful as an adjunct to the clinical diagnosis of familial NF-1 (1) in children less than 6 years of age in whom the full manifestations may not yet be apparent, (2) in NF-1 families interested in prenatal testing, and (3) when the resources available for a complete clinical examination are limited.

Adolescent↗
PubMed2005

[Polyneuropathy associated with neurofibromatosis].

INTRODUCTION: We review the literature on the spectrum of polyneuropathies associated with neurofibromatosis 1 (NF1) and 2 (NF2). BACKGROUND: Symptomatic neuropathies in NF1 are rarer than in NF2, but constitute a potentially severe complication associated with frequent morbidity related to the neuropathy itself, spinal cord compression or peripheral nerve sheath tumor malignant degeneration. Neuropathies are typically observed in young men with subcutaneous neurofibromas (NF1) or cutaneous schwannomas (NF2) and are characterized by a chronic slowly worsening sensorimotor polyneuropathy of the lower limbs. In NF1, demyelinating neuropathy may occur alone or in association with axonal features, whereas in NF2, axonal neuropathies are reported. Large multinodular roots and nerves, which can be easily detected by limb MRI, are characteristic features of NF1-associated polyneuropathies. PERSPECTIVES AND CONCLUSION: Although an associated pathogenic factor may reveal an asymptomatic neuropathy, patients should be monitored carefully because of the increased morbidity and mortality related to the significant proportion of malignant nerve-sheath tumors in these patients with NF1.

Humans↗